PSY4 Depression

Epidemiology of major depressive disorder: • 1 in [blank_start]10[blank_end] primary care patients present with depressive symptoms. • Lifetime risk of depression is 15% and 12 month prevalence is 4.1%. • NZ - 17.9% of [blank_start]women[blank_end] and 10.4% of [blank_start]men[blank_end] • Highest rates in [blank_start]women 35 – 44 years[blank_end] (21%) • Mean age of onset is 27 years with 40% having a first episode by the age of 20 • 54% recover within 6 months, 70% within one year, 12–15% fail to recover and develop a chronic unremitting illness • Economic cost in NZ > $2 billion/year

Match the symptoms/performances affected with their associated regions: PFC, [blank_start]prefrontal cortex;[blank_end] concentration, interest, pleasure, mental fatigue, guilt, worthlessness, suicidality, mood S, striatum; [blank_start]physical fatigue,[blank_end] NA, nucleus accumbens; [blank_start]pleasure, interest, energy[blank_end] HY, hypothalamus; [blank_start]sleep, appetite[blank_end] A, amygdala; [blank_start]guilt, worthlessness, suicidality, mood[blank_end] C, cerebellum; [blank_start]psychomotor[blank_end]

Select from this list of depression symptoms those that overlap with anxiety.

Diagnosis of depression requires ONE of: [blank_start]apathy/anhedonia OR depressed mood[blank_end]. Also requires at least [blank_start]4[blank_end] of: appetite/weight change, sleep disturbances, cognitive [blank_start]dysfunction[blank_end], agitation/restlessness, fatigue, suicidal ideation, worthlessness. Major depressive disorder is the most [blank_start]common[blank_end] mood disorder, defined by occurrence of at least a single major depressive episode - most people experience [blank_start]recurrent[blank_end] episodes.

Pathophysiology: • Inefficient/dysfunctional [blank_start]5-HT, NA and/or DA[blank_end] projections to amygdala and VMPFC are linked to depression • Poor information processing in the [blank_start]cerebellum, striatum[blank_end] and NAc (NA, 5HT and DA projections) linked to psychomotor [blank_start]agitation[blank_end]/retardation • [blank_start]Hypo[blank_end]-active monoaminergic projections from the brain stem to the hypothalamus, basal forebrain and PFC linked to [blank_start]sleep[blank_end] disturbances • Feelings of guilt/worthlessness regulated by amygdala and VMPFC - inefficient or dysfunctional [blank_start]5-HT[blank_end] projections • Suicidal ideation regulated by [blank_start]serotonergic[blank_end] control of the amygdala, VMPFC and [blank_start]orbital frontal[blank_end] cortex (OFC) • Weight and appetite 5-HT projections in the [blank_start]hypothalamus[blank_end]

Why might the clinical effect of SSRIs and SNRIs take several weeks to develop?

Monoamine receptor hypothesis of depression: There is no clear convincing [blank_start]evidence[blank_end] that monoamine deficiency accounts for depression – i.e., there is no “real” monoamine deficit, but increasing monoamines as a treatment is effective. The monoamine [blank_start]receptor[blank_end] hypothesis of depression extends the classic monoamine hypothesis of depression, positing that [blank_start]deficient[blank_end] activity of monoamine [blank_start]neurotransmitters[blank_end] causes [blank_start]up[blank_end]regulation of [blank_start]post[blank_end]synaptic monoamine neurotransmitter [blank_start]receptors[blank_end] which leads to depression.

SSRI mechanisms: - Block 5-HT [blank_start]reuptake[blank_end] pump ([blank_start]SERT[blank_end]) - Increase [blank_start]somatodendritic 5-HT[blank_end] (initially) - Desensitize somatodendritic [blank_start]5-HT1A autoreceptors[blank_end] - Turn on [blank_start]neuronal impulse flow[blank_end] and increase 5-HT [blank_start]release[blank_end] from [blank_start]axon[blank_end] terminals - Finally desensitize [blank_start]postsynaptic 5-HT[blank_end] receptors

Mirtazepine - α2 [blank_start]antagonist[blank_end] - noradrenergic & specific serotonergic antidepressant (also blocks a couple [blank_start]5-HT[blank_end] receptors). • α2-adrenergic receptors are mostly autoreceptors and heteroreceptors which enhance adrenergic and serotonergic neurotransmission. This: a) stops [blank_start]NA[blank_end] turning off its own release ([blank_start]negative[blank_end] feedback) so [blank_start]NA release[blank_end] is increased b) blocks [blank_start]pre[blank_end]synaptic α2 [blank_start]heteroreceptors[blank_end] i.e. the “brakes” on [blank_start]serotonergic[blank_end] neurons, so there is enhanced [blank_start]serotonergic transmission[blank_end] • SEs - somnolence(excess [blank_start]sleepiness[blank_end]), sedation, [blank_start]dry[blank_end] mouth, weight [blank_start]gain[blank_end], increased [blank_start]appetite[blank_end], [blank_start]dizziness[blank_end] and fatigue.

Agomelatine acts as a MT1 and MT2 receptor [blank_start]antagonist[blank_end] (involved in [blank_start]sleep[blank_end]) and 5HT(2C) antagonist. - Stimulation of [blank_start]MT1 and MT2[blank_end] receptors helps [blank_start]resynchronize[blank_end] depression-altered circadian rhythms, which potentially can optimize these changes in monoamines - Binds to [blank_start]5HT2C[blank_end] receptors on [blank_start]GABA[blank_end] interneurons, prevents 5-HT from [blank_start]binding[blank_end] and prevents [blank_start]inhibition[blank_end] of NA and DA release in the [blank_start]prefrontal[blank_end] cortex - ie facilitates their releases.

Venlafaxine (SNRI) - Inhibits [blank_start]5-HT reuptake[blank_end] at low doses and also [blank_start]NA reuptake[blank_end] at increased doses - Converted to active [blank_start]metabolite[blank_end], desvenlafaxine, by [blank_start]CYP[blank_end]2D6 - Desvenlafaxine also inhibits SERT and NAT but its [blank_start]noradrenergic[blank_end] effects are greater than venlafaxine - new drug...

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